Summary Post-traumatic Stress Disorder (PTSD) is among the most prevalent of psychiatric disorders. Trauma exposure is common, including natural disasters, terrorism, wars, automobile crashes, and violent crime. Although the majority of trauma victims experience the symptoms of re-experiencing, avoidance and hyperarousal, for the large majority of such individuals, these symptoms do not become chronic nor do they develop syndromal PTSD. It is critical to identify the underlying neurobiology of PTSD because of the very significant medical and psychiatric morbidity and mortality, and the promise of new therapeutics based on its biological underpinnings. Despite its clinical importance, there have yet to be human biology- focused postmortem studies of well-matched cases and controls to leverage the fact that this is arguably among the best understood Psychiatric Disorder in terms of neural circuit regulation. This proposal utilizes a Linked R01 mechanism across 3-sites (University of Miami (1), Lieber Institute for Brain Development (2), and McLean Hospital with Emory University (3)), to perform a postmortem, multi-omic study of brains from 300 total subjects: PTSD (civilian + military trauma, n=100), mood disorder non-PTSD psychiatric controls (n=100), and normal controls (n=100). We will focus on targeted brain regions with known differential association with PTSD risk as a function of identified intermediate phenotypes, including amygdala, prefrontal cortex and hippocampal dentate gyrus. We will determine differential DNA genotyping / methylation, RNA expression, and Proteomic patterns across brain areas. We hypothesize 1) that known pathways we have previously identified in the periphery and in PTSD models will be differentially identified in the brain regions of PTSD subjects, and 2) that genome- wide exploratory approaches will identify novel epigenetically gene pathways. Our main outcome will be a predictive model of genetic, epigenetic, transcriptomic, and proteomic profiles of brain regions from cases vs. controls. These data will allow an understanding of the region-specific genotype-dependent transcriptional and translational profiles, and findings will be integrated with detailed multi-omic data from other studies. We will use state-of-the-art statistical modeling, combined with rich biological and psychological phenotype measurements to determine a predictive model across conserved brain regions and molecular pathways. This novel, integrated, and impactful linked R01 proposal will lead to the identification of so far unknown trauma-associated genes and proteins, noncoding RNAs, and epigenetic marks in trauma related disorders and will allow the identification of novel therapeutic targets on the level of regulatory RNAs and proteins. Such a strategy has the potential to help redefine psychobiological subtypes of PTSD as well as to reduce the burden of chronic PTSD on our healthcare system.